Contrary to what happens in most preparations of animal tissues where it is necessary to block both NK1 and NK2 receptors to obtain a more efficient antagonism against the spasmogenic effect induced by tachykinins, in other preparations, including preparations of isolated human intestine, the antagonists of NK2 receptor are already fully effective against the spasmogenic effect induced by exogenous or endogenous tachykinins.
In addition to the stimulation role in the regulation of intestinal motility, the activation of tachykinin NK2 receptors, also triggers both intrinsic and extrinsic inhibitory mechanisms to the intestinal wall (Giuliani et al. J. Pharmacol. Exp Ther. 246:322-327 (1988)). Moreover NK2 tachykinin receptors regulate intestinal permeability (Hallgren et al. Am. J. Physiol. 273: G1077-G1086 (1997)) and are also involved in the regulation of the secretion of water and ions in the gut epithelium in rats and in humans (Tough et al. Naunyn-Schmiedeberg's Arch Pharmacol. 367:104-108 (2003), and in the modulation of visceral sensitivity (Julia et al. Gastroenterology 107:94-102 (1994)), especially when altered by an active or previous inflammatory state or by a stressful situation.
These pharmaceutical aspects of tachykinins have suggested the assessment of selective antagonists of the tachykinin NK2 receptor in the development of drugs directed against gastrointestinal diseases characterized by gut motility disorders and visceral hypersensitivity such as, for example, irritable bowel syndrome in adults (Lecci et al. Curr. Opin. Invest. Drugs 3:589-601 (2002)).
Nepadutant is a selective antagonist of the tachykinin NK2 receptor with formula (I), originally described in EP815126. It is bicyclic hexapeptide, with an excellent safety profile and tolerability.
The NK2 antagonist, Nepadutant, can be identified as [N4-(2-acetylamino-2-deoxy-β-D-glucopyranosyl)-L-asparaginyl-L-α-triptophan-L-phenylalanyl-L-2,3-diaminopropio-nil-L-leucil]-C-4.2-N-3.5-lattame-C-1.6-N-2.1-lattame or cyclic[3-amino-L-alanil-L-leucil-N-[2-(acetylamino)-2-deoxy-β-D-glucopyranosyl]-L-asparaginyl-L-α-aspartyl-L-triptophan-L-phenylalanyl](4→1)-lattame (9Cl) (CAS RN: 183747-35-5)) (alternatively known as MEN11420).

Nepadutant has shown good activity in various in vitro and in vivo models and in humans in reversing the side effects of the activation of NK2 receptors in the intestine, such as visceral hyperalgesia or alterations of the intestinal motility.
It has been recently discovered that Nepadutant is absorbed when ad ministered orally in new born animals (rats or mice), contrary to what is found in adult animals. Furthermore, the oral administration of Nepadutant in new born rats is able to block, up to 24 hours after its administration, the increase in intestinal transit induced by the activation of NK2 receptors, without altering the basal parameters. In addition Nepadutant has proven effective in a model of hyperalgesia in new born rats.
These results suggest the oral potential bioavailability even in newborns and therefore the clinical use of Nepadutant in the symptomatic treatment of gastrointestinal disorders (e.g. infantile colic), as claimed in WO2006045820.
The EMA recommends the use of oral solutions for newborns and infants (nurslings) (from 28 days to 23 months) as the preferred dosage form (EMEA/CHMP/PEG/194810/2005). On the other hand the parenteral formulations (e.g. intravenous) are strongly contraindicated especially for not life-threatening diseases. Thus, it was essential to develop an oral solution of Nepadutant for paediatric use in the gastrointestinal disorders.
Nepadutant is poorly soluble in aqueous medium and has a bitter taste. Furthermore, it is stable in the dried state but the solutions of Nepadutant are sensitive to oxidative degradation.
In WO2006045820 pharmaceutical compositions containing paediatric Nepadutant in liquid form are described (pages 7-8, Examples 1-4), and such compositions are characterized by the use of polysorbate as solubilizer; such compositions appear to be not completely satisfactory for their storage limited duration at room temperature or at a high temperature.
EP1464341 describes an ophthalmic solution/emulsion comprising TPGS (Vitamin E TPGS 1000 also referred to as d-alpha tocopheryl polyethylen glycol 1000 succinate) and the antioxidant active ingredient ubiquinone. Combinations of ubiquinone, TPGS and magnesium ascorbyl-2-phosphate show synergistic antioxidant effects. It is not described, however, any antioxidant effect on any active ingredient which is an antagonist of the tachykinin NK2 receptor in solutions containing TPGS.
In WO97/35587 the formation of liquid formulations containing an HIV protease inhibitor, TPGS and a hydrophilic non-aqueous solvent miscible with TPGS is disclosed, preferred for the filling of soft gelatine capsules. The formulations show a higher bioavailability of the HIV protease inhibitor. The non-aqueous solvent is essential for this formulation.
WO99/26607 describes a distribution system based on a liquid crystal structure, in which the drug is dissolved directly in TPGS. In order to maintain the drug in solution the solid structure of cyclosporine with TPGS does not require the presence or absence of emulsifiers, co-solvents, surfactants, or other solubilizer agents. The resulting products, such as controlled release capsules, tablets, pills are solid oral dosage forms. Because TPGS is used as the sole solvent, high amounts of TPGS (50% to 99.9%) are required.
U.S. Pat. No. 5,583,105 describes pre-concentrated emulsion containing the active ingredient cyclosporine in a lipophilic and/or amphiphilic solvent. In this composition TPGS is mentioned as an emulsifier, adjuvant and antioxidant for fat oils. The antioxidant effect on a pharmaceutical active ingredient, and especially on a NK2 receptor antagonist, is not claimed.
WO2006036614 describes materials like surfactants suitable for solid formulations. The TPGS row material of waxy consistency is converted into properly shaped solid that can be incorporated for example into tablets. The use of the solid form for the preparation of solutions and/or emulsions is not described.
EP1216025 describes the use of a wide range of TPGS as a surfactant (from 0.1% to 90%) in solid formulations comprising a dispersant soluble in water and a soluble compound in lipid medium as a lipase inhibitor. The solidified mixture is loaded into HPMC capsules that reveal an increase in the efficiency and power.
Formulations for topical use containing TPGS and layers of alpha-tocopherol to solubilize or emulsify water insoluble drugs are mentioned in WO9531217.
TPGS is described as a stabilizer applied for the formation and stabilization of double-layer liposomes in acid environment (U.S. Pat. No. 5,364,631).
In WO9808490 the preparation of solid co-precipitated for oral delivery of lipophilic substances with poor biodisponibility is described. Delivery tests are conducted on dry powders.